tbuckley/cabot-search huggingface dataset:
Health Effects of Wildfire Smoke Exposure
Authors: Carlos F. Gould, Sam Heft-Neal, Mary Johnson, Juan Aguilera, Marshall Burke, Kari Nadeau
Journal: Annual Review of Medicine (2023)

We review current knowledge on the trends and drivers of global wildfire activity, advances in the measurement of wildfire smoke exposure, and evidence on the health effects of this exposure. We describe methodological issues in estimating the causal effects of wildfire smoke exposures on health and quantify their importance, emphasizing the role of nonlinear and lagged effects. We conduct a systematic review and meta-analysis of the health effects of wildfire smoke exposure, finding positive impacts on all-cause mortality and respiratory hospitalizations but less consistent evidence on cardiovascular morbidity. We conclude by highlighting priority areas for future research, including leveraging recently developed spatially and temporally resolved wildfire-specific ambient air pollution data to improve estimates of the health effects of wildfire smoke exposure.
Recommendations on data sharing in HIV drug resistance research
Authors: Seth C. Inzaule, Mark J. Siedner, Susan J. Little, Santiago Avila-Rios, Alisen Ayitewala, Ronald J. Bosch, Vincent Calvez, Francesca Ceccherini-Silberstein, Charlotte Charpentier, Diane Descamps, Susan H. Eshleman, Joseph Fokam, Lisa M. Frenkel, Ravindra K. Gupta, John P.A. Ioannidis, Pontiano Kaleebu, Rami Kantor, Seble G. Kassaye, Sergei L. Kosakovsky Pond, Vinie Kouamou, Roger D. Kouyos, Daniel R. Kuritzkes, Richard Lessells, Anne-Genevieve Marcelin, Lawrence Mbuagbaw, Brian Minalga, Nicaise Ndembi, Richard A. Neher, Roger Paredes, Deenan Pillay, Elliot G. Raizes, Soo-Yon Rhee, Douglas D. Richman, Kiat Ruxrungtham, Pardis C. Sabeti, Jonathan M. Schapiro, Sunee Sirivichayakul, Kim Steegen, Wataru Sugiura, Gert U. van Zyl, Anne-Mieke Vandamme, Annemarie M.J. Wensing, Joel O. Wertheim, Huldrych F. Gunthard, Michael R. Jordan, Robert W. Shafer
Journal: PLoS Medicine (2023)

Author summary • Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the development of HIV drug resistance leads to the requirement for antiretroviral drugs that may be less effective, less well-tolerated, and more expensive than those used in first-line regimens. • HIV drug resistance studies are designed to determine which HIV mutations are selected by antiretroviral drugs and, in turn, how these mutations affect antiretroviral drug susceptibility and response to future antiretroviral treatment regimens. • Such studies collectively form a vital knowledge base essential for monitoring global HIV drug resistance trends, interpreting HIV genotypic tests, and updating HIV treatment guidelines. • Although HIV drug resistance data are collected in many studies, such data are often not publicly shared, prompting the need to recommend best practices to encourage and standardize HIV drug resistance data sharing. • In contrast to other viruses, sharing HIV sequences from phylogenetic studies of transmission dynamics requires additional precautions as HIV transmission is criminalized in many countries and regions. • Our recommendations are designed to ensure that the data that contribute to HIV drug resistance knowledge will be available without undue hardship to those publishing HIV drug resistance studies and without risk to people living with HIV.
Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling
Authors: Ruth Shiloh, Ruth Lubin, Odeya David, Ifat Geron, Elimelech Okon, Idit Hazan, Marketa Zaliova, Gil Amarilyo, Yehudit Birger, Yael Borovitz, Dafna Brik, Arnon Broides, Sarit Cohen-Kedar, Liora Harel, Eyal Kristal, Daria Kozlova, Galina Ling, Mika Shapira Rootman, Noa Shefer Averbuch, Shiri Spielman, Jan Trka, Shai Izraeli, Simon Yona, Sarah Elitzur
Journal: Blood (2023)
Re: Gabriela Ilie, Ricardo Rendon, Ross Mason, et al. A Comprehensive 6-mo Prostate Cancer Patient Empowerment Program Decreases Psychological Distress Among Men Undergoing Curative Prostate Cancer Treatment: A Randomized Clinical Trial. Eur Urol 2023;83:561–70
Authors: Matthias May, Ingmar Wolff, Sabine D. Brookman-May
Journal: European Urology (2023)
Reply to Matthias May, Ingmar Wolff, and Sabine D. Brookman-May’s Letter to the Editor re: Gabriela Ilie, Ricardo Rendon, Ross Mason, et al. A Comprehensive 6-mo Prostate Cancer Patient Empowerment Program Decreases Psychological Distress Among Men Undergoing Curative Prostate Cancer Treatment: A Randomized Clinical Trial. Eur Urol 2023;83:561–70
Authors: Gabriela Ilie, Robert David Harold Rutledge
Journal: European Urology (2023)
Reply to André Pontes-Silva’s Letter to the Editor re: Gabriela Ilie, Ricardo Rendon, Ross Mason, et al. A Comprehensive 6-mo Prostate Cancer Patient Empowerment Program Decreases Psychological Distress Among Men Undergoing Curative Prostate Cancer Treatment: A Randomized Clinical Trial. Eur Urol 2023;83:561–70
Authors: Gabriela Ilie, Robert David Harold Rutledge
Journal: European Urology (2023)
Environmental forcing alters fisheries selection
Authors: Davide Thambithurai, Anna Kuparinen
Journal: Trends in Ecology & Evolution (2023)

Fishing-induced evolution (FIE) threatens the ecology, resilience, and economic value of fish populations. Traits under selection, and mechanisms of selection, can be influenced by abiotic and biotic perturbations, yet this has been overlooked. Here, we present the fishery selection continuum, where selection ranges from rigid fisheries selection to flexible fisheries selection. We provide examples on how FIE may function along this continuum, and identify selective processes that should be considered less or more flexible. We also introduce fishery reaction norms, which serve to conceptualise how selection from fishing may function in a dynamic context. Ultimately, we suggest an integrative approach to studying FIE that considers the environmental conditions in which it functions.
Ending communicable diseases requires a combined elimination framework
Authors: Jose Ramos-Horta, Poonam Khetrapal Singh
Journal: BMJ (2023)

A multi-sector combined framework for the elimination of communicable diseases, co-designed with affected communities, is urgently needed to end communicable disease and meet the 2030 sustainable development goals for health, argue Jose Ramos-Horta and Poonam Khetrapal Singh
Evolutionary Analyses of Gene Expression Divergence in <i>Panicum hallii</i>: Exploring Constitutive and Plastic Responses Using Reciprocal Transplants
Authors: Govinal Badiger Bhaskara, Taslima Haque, Jason E Bonnette, Joseph D Napier, Diane Bauer, Jeremy Schmutz, Thomas E Juenger
Journal: Molecular Biology and Evolution (2023)

The evolution of gene expression is thought to be an important mechanism of local adaptation and ecological speciation. Gene expression divergence occurs through the evolution of cis- polymorphisms and through more widespread effects driven by trans-regulatory factors. Here, we explore expression and sequence divergence in a large sample of Panicum hallii accessions encompassing the species range using a reciprocal transplantation experiment. We observed widespread genotype and transplant site drivers of expression divergence, with a limited number of genes exhibiting genotype-by-site interactions. We used a modified FST-QST outlier approach (QPC analysis) to detect local adaptation. We identified 514 genes with constitutive expression divergence above and beyond the levels expected under neutral processes. However, no plastic expression responses met our multiple testing correction as QPC outliers. Constitutive QPC outlier genes were involved in a number of developmental processes and responses to abiotic environments. Leveraging earlier expression quantitative trait loci results, we found a strong enrichment of expression divergence, including for QPC outliers, in genes previously identified with cis and cis-environment interactions but found no patterns related to trans-factors. Population genetic analyses detected elevated sequence divergence of promoters and coding sequence of constitutive expression outliers but little evidence for positive selection on these proteins. Our results are consistent with a hypothesis of cis-regulatory divergence as a primary driver of expression divergence in P. hallii.
Inference of Coalescence Times and Variant Ages Using Convolutional Neural Networks
Authors: Juba Nait Saada, Zoi Tsangalidou, Miriam Stricker, Pier Francesco Palamara
Journal: Molecular Biology and Evolution (2023)

Accurate inference of the time to the most recent common ancestor (TMRCA) between pairs of individuals and of the age of genomic variants is key in several population genetic analyses. We developed a likelihood-free approach, called CoalNN, which uses a convolutional neural network to predict pairwise TMRCAs and allele ages from sequencing or SNP array data. CoalNN is trained through simulation and can be adapted to varying parameters, such as demographic history, using transfer learning. Across several simulated scenarios, CoalNN matched or outperformed the accuracy of model-based approaches for pairwise TMRCA and allele age prediction. We applied CoalNN to settings for which model-based approaches are under-developed and performed analyses to gain insights into the set of features it uses to perform TMRCA prediction. We next used CoalNN to analyze 2,504 samples from 26 populations in the 1,000 Genome Project data set, inferring the age of ∼80 million variants. We observed substantial variation across populations and for variants predicted to be pathogenic, reflecting heterogeneous demographic histories and the action of negative selection. We used CoalNN's predicted allele ages to construct genome-wide annotations capturing the signature of past negative selection. We performed LD-score regression analysis of heritability using summary association statistics from 63 independent complex traits and diseases (average N=314k), observing increased annotation-specific effects on heritability compared to a previous allele age annotation. These results highlight the effectiveness of using likelihood-free, simulation-trained models to infer properties of gene genealogies in large genomic data sets.
Vedolizumab, Adalimumab, and Methotrexate Combination Therapy in Crohn’s Disease (EXPLORER)
Authors: Jean-Frederic Colombel, Ryan C. Ungaro, Bruce E. Sands, Corey A. Siegel, Douglas C. Wolf, John F. Valentine, Brian G. Feagan, Blue Neustifter, Harisha Kadali, Pradeep Nazarey, Alexandra James, Vipul Jairath, Rana M. Qasim Khan
Journal: Clinical Gastroenterology and Hepatology (2023)

BACKGROUND & AIMS Although biologics have revolutionized treatment of Crohn's disease (CD), an efficacy ceiling has been reached. Combining biologic therapies may improve remission rates. METHODS EXPLORER, a phase 4, single-arm, open-label study, evaluated triple combination therapy with vedolizumab (300 mg on day 1, weeks 2 and 6, then every 8 weeks), adalimumab (160 mg on day 2, 80 mg at week 2, then 40 mg every 2 weeks), and methotrexate (15 mg weekly) in biologic-naïve patients with newly diagnosed, moderate- to high-risk CD. Endoscopic remission at week 26 (primary end point; Simple Endoscopic Score for Crohn's Disease [SES-CD] ≤2), clinical remission at weeks 10 and 26 (secondary end point; Crohn's Disease Activity Index [CDAI] <150), and incidences of adverse events and serious adverse events (SAEs) were evaluated. RESULTS Among 55 enrolled patients, mean CD duration was 0.4 years, mean baseline SES-CD was 12.6, and mean baseline CDAI was 265.5. At week 26, 19 patients (34.5%) were in endoscopic remission. At weeks 10 and 26, 34 (61.8%) and 30 patients (54.5%), respectively, were in clinical remission. Post hoc Bayesian analysis demonstrated that the probabilities that triple combination therapy produced a higher endoscopic remission rate (33.5%; 95% credible interval, 22.4–45.7) than placebo (14%), vedolizumab monotherapy (27%), or adalimumab monotherapy (30%) were ≥99.9%, 86.3%, and 71.4%, respectively. Six patients had SAEs. CONCLUSIONS Combination therapy resulted in endoscopic and clinical remission at week 26 in 34.5% and 54.5% of patients, respectively, with no safety signal related to the treatment regimen. This supports further evaluation of combination therapy in CD. ClinicalTrials.gov number: NCT02764762.
Discovery of a Novel Missense Variant in <scp><i>NLRP3</i></scp> Causing Atypical <scp>Cryopyrin‐Associated</scp> Periodic Syndromes With Hearing Loss as the Primary Presentation, Responsive to Anti–Interleukin‐1 Therapy
Authors: Merav Birk‐Bachar, Hadar Cohen, Efrat Sofrin‐Drucker, Nesia Kropach‐Gilad, Naama Orenstein, Gabriel Lidzbarsky, Liora Kornreich, Rotem Tal, Gil Amarilyo, Yoel Levinsky, Meirav Sokolov, Eyal Raveh, Motti Gerlic, Liora Harel
Journal: Arthritis & Rheumatology (2023)

Objective Cryopyrin‐associated periodic syndromes (CAPS), also known as NLRP3‐associated autoinflammatory diseases, are a spectrum of rare autoinflammatory diseases caused by gain‐of‐function variants in the NLRP3 gene, resulting in inflammasome hyperactivation and dysregulated release of interleukin‐1β (IL‐1β). Many patients with CAPS develop progressive sensorineural hearing loss (SNHL) because of cochlear autoinflammation, which may be the sole manifestation in rare cases. This study was undertaken to establish the suspected diagnosis of CAPS in a family presenting with autosomal‐dominant progressive/acute SNHL and a novel missense variant in the NLRP3 gene of unknown significance (NM_001079821.3:c.1784G&gt;A p.Ser595Asn). Methods We conducted an ex vivo functional assessment of the NLRP3 inflammasome in heterozygous individuals (n = 10) and healthy family members (n = 5). Results The assay revealed hyperactivation of the inflammasome among heterozygous individuals, supporting the hypothesis that this missense variant is a pathogenic gain‐of‐function variant. Administration of IL‐1 receptor antagonist resulted in a substantial clinical improvement among pediatric patients, who exhibited near resolution of hearing impairment within 1 to 3 months of treatment. Conclusion Our findings highlight the crucial role of early diagnosis and treatment with an anti–IL‐1 agent in reversing cochlear damage. Furthermore, our results suggest that high‐ and ultrahigh‐frequency ranges need to be included in the auditory assessment to enable early detection of subclinical SNHL. Finally, incorporating functional inflammasome assessment as part of the clinical evaluation could establish the diagnosis in inconclusive cases. image
Dermatological toxicities induced by T-cell-redirecting G protein-coupled receptor family C class 5 member D bispecific antibody talquetamab
Authors: Marion Lery, Aurore Perrot, Ariadna Ortiz-Brugués, Emmanuelle Vigarios, Diana Anghel, Pierre Bories, Vincent Sibaud
Journal: Journal of the American Academy of Dermatology (2023)
GRK2 inhibits Flt-1+ macrophage infiltration and its proangiogenic properties in rheumatoid arthritis
Authors: Xuezhi Yang, Yingjie Zhao, Qi Wei, Xuemin Zhu, Luping Wang, Wankang Zhang, Xiaoyi Liu, Jiajie Kuai, Fengling Wang, Wei Wei
Journal: Acta Pharmaceutica Sinica B (2023)

Rheumatoid arthritis (RA) is an autoimmune disease with a complex etiology. Monocyte-derived macrophages (MDMs) infiltration are associated with RA severity. We have reported the deletion of G-protein-coupled receptor kinase 2 (GRK2) reprograms macrophages toward an anti-inflammatory phenotype by recovering G-protein-coupled receptor signaling. However, as more GRK2-interacting proteins were discovered, the GRK2 interactome mechanisms in RA have been understudied. Thus, in the collagen-induced arthritis mouse model, we performed genetic GRK2 deletion using GRK2f/fLyz2-Cre+/‒ mice. Synovial inflammation and M1 polarization were improved in GRK2f/fLyz2-Cre+/‒ mice. Supporting experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptor γ (PPARγ) as a new GRK2-interacting protein. We further confirmed that fms-related tyrosine kinase 1 (Flt-1), which promoted macrophage migration to induce angiogenesis, was inhibited by GRK2-PPARγ signaling. Mechanistically, excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPARγ ligand-binding domain and enhanced Flt-1 transcription. Furthermore, the treatment of mice with GRK2 activity inhibitor resulted in significantly diminished CIA pathology, Flt-1+ macrophages induced-synovial inflammation, and angiogenesis. Altogether, we anticipate to facilitate the elucidation of previously unappreciated details of GRK2-specific intracellular signaling. Targeting GRK2 activity is a viable strategy to inhibit MDMs infiltration, affording a distinct way to control joint inflammation and angiogenesis of RA.
Non-Small Cell Lung Cancer Epigenomes Exhibit Altered DNA Methylation in Smokers and Never-Smokers
Authors: Jennifer A. Karlow, Erica C. Pehrsson, Xiaoyun Xing, Mark Watson, Siddhartha Devarakonda, Ramaswamy Govindan, Ting Wang
Journal: Genomics Proteomics & Bioinformatics (2023)

Abstract Epigenetic alterations are widespread in cancer and can complement genetic alterations to influence cancer progression and treatment outcome. To determine the potential contribution of DNA methylation alterations to tumor phenotype in non-small cell lung cancer (NSCLC) in both smoker and never-smoker patients, we performed genome-wide profiling of DNA methylation in 17 primary NSCLC tumors and 10 matched normal lung samples using the complementary assays, methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylation sensitive restriction enzyme sequencing (MRE-seq). We reported recurrent methylation changes in the promoters of several genes, many previously implicated in cancer, including FAM83A and SEPT9 (hypomethylation), as well as PCDH7, NKX2-1, and SOX17 (hypermethylation). Although many methylation changes between tumors and their paired normal samples were shared across patients, several were specific to a particular smoking status. For example, never-smokers displayed a greater proportion of hypomethylated differentially methylated regions (hypoDMRs) and a greater number of recurrently hypomethylated promoters, including those of ASPSCR1, TOP2A, DPP9, and USP39, all previously linked to cancer. Changes outside of promoters were also widespread and often recurrent, particularly methylation loss over repetitive elements, highly enriched for ERV1 subfamilies. Recurrent hypoDMRs were enriched for several transcription factor binding motifs, often for genes involved in signaling and cell proliferation. For example, 71% of recurrent promoter hypoDMRs contained a motif for NKX2-1. Finally, the majority of DMRs were located within an active chromatin state in tissues profiled using the Roadmap Epigenomics data, suggesting that methylation changes may contribute to altered regulatory programs through the adaptation of cell type-specific expression programs.
Macrophage LMO7 deficiency facilitates inflammatory injury via metabolic-epigenetic reprogramming
Authors: Shixin Duan, Xinyi Lou, Shiyi Chen, Hongchao Jiang, Dongxin Chen, Rui Yin, Mengkai Li, Yuseng Gou, Wenjuan Zhao, Lei Sun, Feng Qian
Journal: Acta Pharmaceutica Sinica B (2023)

Inflammatory bowel disease (IBD) is a formidable disease due to its complex pathogenesis. Macrophages, as a major immune cell population in IBD, are crucial for gut homeostasis. However, it is still unveiled how macrophages modulate IBD. Here, we found that LIM domain only 7 (LMO7) was downregulated in pro-inflammatory macrophages, and that LMO7 directly degraded 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) through K48-mediated ubiquitination in macrophages. As an enzyme that regulates glycolysis, PFKFB3 degradation led to the glycolytic process inhibition in macrophages, which in turn inhibited macrophage activation and ultimately attenuated murine colitis. Moreover, we demonstrated that PFKFB3 was required for histone demethylase Jumonji domain-containing protein 3 (JMJD3) expression, thereby inhibiting the protein level of trimethylation of histone H3 on lysine 27 (H3K27me3). Overall, our results indicated the LMO7/PFKFB3/JMJD3 axis is essential for modulating macrophage function and IBD pathogenesis. Targeting LMO7 or macrophage metabolism could potentially be an effective strategy for treating inflammatory diseases.
Sensitivity, Specificity, and Cutoff Identifying Optic Atrophy by Macular Ganglion Cell Layer Volume in Syndromic Craniosynostosis
Authors: Yoon-Hee Chang, Steven J. Staffa, Leyla Yavuz Saricay, David Zurakowski, Ryan Gise, Linda R. Dagi
Journal: Ophthalmology (2023)

PurposeDetermine sensitivity, specificity, and cut-off of macular ganglion cell layer (GCL) volume consistent with optic atrophy in children with syndromic craniosynostosis (CS). Investigate whether obstructive sleep apnea (OSA), Chiari malformation, history of elevated intracranial pressure (ICP), CS diagnosis, age, or sex independently alter GCL volume with CS.DesignRetrospective cross-sectional study.SubjectsPatients with syndromic CS evaluated at Boston Children's Hospital (2010 – 2022) with reliable macular optical coherence tomography (OCT) scans.MethodsLatest ophthalmic examination that included OCT macula scans was identified. Age at examination, sex, ethnicity, best-corrected logMAR visual acuity, cycloplegic refraction, and funduscopic optic nerve appearance were recorded in addition to history of primary or recurrent elevated ICP, Chiari malformation and OSA. Spectral domain-OCT software quantified segmentation of macula retinal layers, and was manually checked.Main Outcome MeasuresPrimary outcome was determining sensitivity, specificity and optimal cutoff of GCL volume consistent with optic atrophy. Secondary outcome was determining possible independent association of previously elevated ICP, OSA, Chiari, CS diagnosis, logMAR acuity, age, or sex with altered GCL volume.ResultsMedian age at examination was 11.9 years (interquartile range (IQR), 8.5-14.8 years). Fifty-eight of 61 patients had reliable macula scans, 74% were female, and diagnoses were Apert (n=14); Crouzon (n=17); Muenke (n=6); Pfeiffer (n= 6); and Saethre-Chotzen (n=15). Optimal cutoff identifying optic atrophy was GCL volume <1.02mm3 with a sensitivity of 83% and specificity of 77%. Univariate analysis demonstrated significantly lower macular GCL volume with optic atrophy on fundus exam (P<0.001), Apert syndrome (P<0.001), history of elevated ICP (P=0.015), Chiari malformation (P=0.001), OSA (P<0.001), in males (P=0.027) and with worse logMAR acuity (-0.36, P<0.001). Multivariable median regression analysis confirmed that only OSA (P=0.005), optic atrophy on fundus exam (P=0.003), and worse logMAR acuity (P=0.042) independently associated with lower GCL volume.ConclusionsMacular GCL volume <1.02mm3 predicted optic atrophy in patients with CS with sensitive of 83% and specificity of 77%. OSA, a treatable often concomitant disorder, was independently associated with lower GCL volume. Surveillance for optic neuropathy by GCL volume proved effective in a population where cognitive skills can limit acquisition of other key ophthalmic measures.